The leukotrienes are extremely potent substances which produce a wide variety of biological effects, often even when present only in nanomolar to picomolar concentrations. Leukotrienes are important pathological mediators in a variety of diseases. Alterations in leukotriene metabolism have been demonstrated in a number of disease states including asthma, allergic rhinitis, rheumatoid arthritis and gout, psoriasis, adult respiratory distress syndrome, inflammatory bowel disease, endotoxin shock syndrome, atherosclerosis, ischemia induced myocardial injury, and central nervous system pathology resulting from the formation of leukotrienes following stroke or subarachnoid hemorrhage.
The enzyme 5-lipoxygenase catalyzes the first step leading to the biosynthesis of all the leukotrienes and therefore inhibition of this enzyme provides an approach to limit the effects of all the products of this pathway. Agents capable of abrogating the effects of these potent mediators of pathophysiological processes represent a promising class of therapeutic agents (Brooks, D. W., Bell, R. L., and Carter, G. W., in Annual Reprots in Medicinal Chemistry, Chapter 8. Pulmonary and Antiallergy Agents, Allen, R. C. ed., Academic Press, 1988).
Toward this end, several new agents have been developed which are useful as leukotriene biosynthesis inhibitors. For example, U.S. Pat. No. 4,970,215 to Mohrs, et al. discloses and claims certain 4-(quinolin-2-yl-methoxy)phenylcycloalkyl acetic acids for inhibition of leukotriene synthesis. European Patent Application 0 349 062 to Zamboni et al. discloses and claims certain quinolylmethoxyphenyl substituted thioalkanoic acid derivatives having leukotriene biosynthesis inhibitory activity. The publication of Prasit, et al. in "Bioorganic and Medicinal Chemistry Letter, 1: 645-648 describes a new potent and orally active leukotriene synthesis inhibitor, L-674,636 ({[4-(4-chlorophenyl)-1-(4-[2-quinolinylmethoxyphenyl)butyl]thio}acetic acid). U.S. Pat. No. 5,358,955 to Brooks, et al. discloses and claims certain pyridyl-, quinolyl- and naphthylmethoxyphenyl compounds which inhibit lipoxygenase activity. Most recently, U.S. Pat. No. 5,399,699 to Kolasa, et al. discloses and claims certain substituted indole iminooxy derivatives which also act as inhibitors of leukotriene biosynthesis.